title: Simvastatin re-couples dysfunctional endothelial nitric oxide synthase in experimental subarachnoid hemorrhage.
abstract: Reduced endothelial nitric oxide synthase (eNOS) function has been linked to secondary complications of subarachnoid hemorrhage (SAH). We previously found that there is increased eNOS function after SAH but that it is uncoupled, leading to secondary complications such as vasospasm, microthromboembolism and neuronal apoptosis. Here we test the hypothesis that recoupling eNOS with simvastatin can prevent these complications. SAH was created in mice that were treated with vehicle or simvastatin starting 2 weeks before or 30 minutes after SAH. SAH increased phosphorylated eNOS which was prevented by pre- or post-treatment with simvastatin. Simvastatin pre-treatment also prevented the increase in eNOS monomer formation that was associated with SAH, decreased superoxide anion radical production and increased NO. These changes were associated with decreased vasospasm, microthromboemboli and neuronal injury. The data suggest that simvastatin re-couples eNOS after SAH, leading to decreased secondary complications such as vasospasm, microthromboemboli and neuronal injury.
authors.affiliation: Division of Neurosurgery, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Sabri
authors.forename: Jinglu
authors.initials: J
authors.lastname: Ai
authors.forename: Philip A
authors.initials: PA
authors.lastname: Marsden
authors.forename: R Loch
authors.initials: RL
authors.lastname: Macdonald
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007763:Lac Operon; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D013345:Subarachnoid Hemorrhage / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009569:Nitric Oxide; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III